In rats with a unilateral lesion of the dopaminergic nigrostriatal pathway with 6-hydroxydopamine, blockade of N-methyl-D-aspartate receptors by MK-801 strongly potentiated the turning behavior induced by D-1 receptor stimulation. To determine the functional consequences of such positive interaction we measured the local rates of cerebral glucose utilization (lCMRglc) in lesioned rats treated with MK-801(0.1 mgkg) and the D-1 agonist SKF 38393 (1.5 mgkg), either alone or in combination. Treatment with each drug separately did not induce any substantial change in lCMR,, besides an increase in the metabolic activity of the dorsomedial caudate and entopeduncular nucleus (EP) of the lesioned side of MK-801 treated rats, as compared to the same side of lesioned rats treated with vehicle. Combined administration of MK-801 + SKF 38393 increased 1CMRgIc in the EP (+77%) and in the substantia nigra pars reticulata (SNr) (+30%) of the lesioned side as compared with the intact side, while it decreased lCMRglc in the lateral habenula (-26%). These changes were also significant when compared to the lesioned side of vehicle treated rats. The results suggest that while the caudate putamen might be the primary site of MK-801 and SKF 38393 positive interaction, the EP and SNr are the striatal efferent areas where this positive interaction is expressed. o 1992 Wiley-Liss, Inc.